CN110759942A - Method for industrially producing choline alfoscerate - Google Patents
Method for industrially producing choline alfoscerate Download PDFInfo
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- CN110759942A CN110759942A CN201810827949.7A CN201810827949A CN110759942A CN 110759942 A CN110759942 A CN 110759942A CN 201810827949 A CN201810827949 A CN 201810827949A CN 110759942 A CN110759942 A CN 110759942A
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- choline
- propanediol
- choline alfoscerate
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- 239000008777 Glycerylphosphorylcholine Substances 0.000 title claims abstract description 38
- 238000000034 method Methods 0.000 title claims abstract description 31
- 229960004788 choline alfoscerate Drugs 0.000 title claims abstract description 30
- SUHOQUVVVLNYQR-MRVPVSSYSA-O glycerylphosphorylcholine Chemical compound C[N+](C)(C)CCO[P@](O)(=O)OC[C@H](O)CO SUHOQUVVVLNYQR-MRVPVSSYSA-O 0.000 title abstract 4
- 239000011347 resin Substances 0.000 claims abstract description 53
- 229920005989 resin Polymers 0.000 claims abstract description 53
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 229910052751 metal Inorganic materials 0.000 claims abstract description 21
- 239000002184 metal Substances 0.000 claims abstract description 21
- 229960004063 propylene glycol Drugs 0.000 claims abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 18
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims abstract description 17
- 239000000758 substrate Substances 0.000 claims abstract description 7
- SUHOQUVVVLNYQR-MRVPVSSYSA-N choline alfoscerate Chemical compound C[N+](C)(C)CCOP([O-])(=O)OC[C@H](O)CO SUHOQUVVVLNYQR-MRVPVSSYSA-N 0.000 claims description 34
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 25
- PYJNAPOPMIJKJZ-UHFFFAOYSA-N phosphorylcholine chloride Chemical class [Cl-].C[N+](C)(C)CCOP(O)(O)=O PYJNAPOPMIJKJZ-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 239000000047 product Substances 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 239000003513 alkali Substances 0.000 claims description 13
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 150000002191 fatty alcohols Chemical class 0.000 claims description 12
- 239000012535 impurity Substances 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- 229950004354 phosphorylcholine Drugs 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- YKYOUMDCQGMQQO-UHFFFAOYSA-L cadmium dichloride Chemical compound Cl[Cd]Cl YKYOUMDCQGMQQO-UHFFFAOYSA-L 0.000 claims description 8
- 239000008367 deionised water Substances 0.000 claims description 8
- 229910021641 deionized water Inorganic materials 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 8
- 239000011345 viscous material Substances 0.000 claims description 8
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims description 8
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 8
- SSZWWUDQMAHNAQ-VKHMYHEASA-N (R)-3-chloro-1,2-propanediol Chemical compound OC[C@@H](O)CCl SSZWWUDQMAHNAQ-VKHMYHEASA-N 0.000 claims description 7
- 239000001763 2-hydroxyethyl(trimethyl)azanium Substances 0.000 claims description 6
- 235000019743 Choline chloride Nutrition 0.000 claims description 6
- 229960003178 choline chloride Drugs 0.000 claims description 6
- SGMZJAMFUVOLNK-UHFFFAOYSA-M choline chloride Chemical compound [Cl-].C[N+](C)(C)CCO SGMZJAMFUVOLNK-UHFFFAOYSA-M 0.000 claims description 6
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical group [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 5
- 239000011575 calcium Substances 0.000 claims description 5
- 229910052791 calcium Inorganic materials 0.000 claims description 5
- 239000003480 eluent Substances 0.000 claims description 5
- 239000003456 ion exchange resin Substances 0.000 claims description 5
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 5
- 239000011591 potassium Substances 0.000 claims description 5
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical group [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 4
- 239000001110 calcium chloride Substances 0.000 claims description 4
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 229960004956 glycerylphosphorylcholine Drugs 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 claims description 4
- 229910001623 magnesium bromide Inorganic materials 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- ZTLQZAKIWSXKFB-UHFFFAOYSA-M sodium;2-(trimethylazaniumyl)ethyl phosphate Chemical compound [Na+].C[N+](C)(C)CCOP([O-])([O-])=O ZTLQZAKIWSXKFB-UHFFFAOYSA-M 0.000 claims description 4
- 229940102001 zinc bromide Drugs 0.000 claims description 4
- 239000011592 zinc chloride Substances 0.000 claims description 4
- 235000005074 zinc chloride Nutrition 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- ITVPBBDAZKBMRP-UHFFFAOYSA-N chloro-dioxido-oxo-$l^{5}-phosphane;hydron Chemical compound OP(O)(Cl)=O ITVPBBDAZKBMRP-UHFFFAOYSA-N 0.000 claims 1
- 229960001231 choline Drugs 0.000 claims 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims 1
- 150000001450 anions Chemical class 0.000 abstract description 4
- 150000001768 cations Chemical class 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000002904 solvent Substances 0.000 abstract description 3
- 230000003287 optical effect Effects 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol group Chemical group OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 7
- 238000000746 purification Methods 0.000 description 6
- 238000009776 industrial production Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- SIBFQOUHOCRXDL-VKHMYHEASA-N (2r)-3-bromopropane-1,2-diol Chemical compound OC[C@@H](O)CBr SIBFQOUHOCRXDL-VKHMYHEASA-N 0.000 description 3
- GLJRUXJFSCIQFV-VKHMYHEASA-N (2r)-3-iodopropane-1,2-diol Chemical compound OC[C@@H](O)CI GLJRUXJFSCIQFV-VKHMYHEASA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- FDENRCWNQMDNDG-UHFFFAOYSA-N hex-3-ene-1,2,3-triol Chemical compound CCC=C(O)C(O)CO FDENRCWNQMDNDG-UHFFFAOYSA-N 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 125000001924 fatty-acyl group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000011630 iodine Chemical group 0.000 description 1
- 229910052740 iodine Chemical group 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
Abstract
The invention discloses a method for industrially producing choline alfoscerate, which takes choline alfoscerate and (R) - (-) -3-halo-1, 2-propanediol as substrates, reacts in lower aliphatic alcohol, and is purified by a halogenated metal salt modified resin column and anion and cation resin respectively, thus obtaining the choline alfoscerate with higher purity, the method takes lower aliphatic alcohol and water as solvents from the industrial angle, and the lower aliphatic alcohol and the water are completely reused, which extremely accords with the modern green chemical concept, the production cost is reduced, the modified resin column is primarily purified, and the anion and cation resin column is finally purified, compared with the prior industrial technology, the technology provided by the invention has the advantages of environmental protection, simple operation, low cost, the yield of more than 85 percent, the purity of more than 99 percent, and the optical rotation of-2.4 to-2.9, the pH is 5.0 to 7.0.
Description
Technical Field
The invention relates to the technical field of chemical industry, in particular to a method for industrially producing choline alfoscerate.
Background
Unlike drugs that inhibit the breakdown of acetylcholine, choline alfoscerate is a product of complete hydrolysis of the two fatty acyl groups on the phosphatidylcholine molecule, which stimulates the body to produce new phosphatidylcholine. It is often used in the brain for degenerative nervous syndrome or secondary cerebral insufficiency, especially manifested by primary cognitive disorder or secondary memory impairment, disorientation and disappearance, reduced activity and enthusiasm and attention deficit in the elderly, and also in emotional and behavioral abnormalities in the elderly, such as: unstable mood, irritability, mild response to changes in the surrounding environment, and senile pseudo-depression.
The source of choline alfoscerate mainly depends on enzymatic hydrolysis and purification after being extracted from natural substances, so that the industrial cost is greatly increased.
In recent years, a plurality of scholars at home and abroad continuously explore the chemical synthesis method of choline alfoscerate and form a plurality of feasible routes.
EP patent EPOS86100, the hydroxyl groups at 1, 2-position of glycerol are protected to prepare propylidene glycerol, the propylidene glycerol is reacted with 2-oxo-2-chloro-1, 3, 2-phospholane to prepare L- α -isopropylidene-3-glycerol cyclohexanephosphoryl ester, then the L- α -isopropylidene-3-glycerol cyclohexanephosphoryl ester is condensed with trimethylamine in a pressure reaction kettle to obtain L- α -isopropylidene glycerophosphoryl ester, then the L- α -isopropylidene glycerophosphoryl ester is subjected to ring opening in diluted hydrochloric acid to obtain a choline glycerophosphate crude product, and finally the choline glycerophosphate pure product is purified by ion exchange resin.
WO2007/145476 adopts chiral glycidol as a starting material to be condensed with phosphoryl choline in the presence of isopropanol, and choline alfoscerate is obtained through resin purification.
Patent CN201010276526.4 proposes a simpler route, directly adopts 3-halogeno-1, 2-propylene glycol as raw material to directly react with phosphorylcholine or phosphorylcholine salt in absolute ethanol, then uses acetone to remove impurities after concentrating the reaction liquid, and then uses ethanol to crystallize to obtain a pure product.
The route provided by the scheme is simple and easy to operate, but after industrial scale-up, a plurality of problems exist:
1. the phosphorylcholine salt is prepared, the requirement of moisture can not be met through simple evaporation, the decomposition of 3-halogenated-1, 2-propylene glycol is accelerated during the reaction, and the yield is reduced;
2. the effect is not good enough by simple acetone impurity removal, and only part of glycerin impurities can be removed;
3. the impurity content is high, so that the product is difficult to crystallize, the crystallization rate is not high, and some by-products similar to the product can be wrapped in the product and crystallized together, thereby seriously affecting the quality of the product.
Disclosure of Invention
The invention aims to provide a method for industrially producing choline alfoscerate, which solves the problems in the background art.
In order to solve the technical problems, the invention provides the following technical scheme: an industrial production method of choline glycerophosphate uses chlorinated choline phosphate and (R) - (-) -3-halogeno-1, 2-propanediol as substrates, and makes them react in lower aliphatic alcohol, and respectively uses halogenated metal salt modified resin column and anion-cation resin to make purification so as to obtain the high-purity choline glycerophosphate.
The method mainly comprises the following steps:
1) choline chloride potassium phosphate and (R) - (-) -3-chloro-1, 2-propanediol in a molar ratio of 1: 1.5, mixing, reacting in a low-grade fatty alcohol solution, performing reflux reaction for 24-48 hours, and centrifuging to obtain a filtrate;
2) distilling off low-grade fatty alcohol in the filtrate, and recovering the low-grade fatty alcohol to obtain a viscous material;
3) adding deionized water to dissolve the viscous material, adding activated carbon to decolorize, and filtering to obtain water solution;
4) passing through a halogenated metal salt modified resin column, eluting impurities by deionized water, eluting a 5% hydrochloric acid eluate to obtain a product, and collecting the hydrochloric acid eluate;
5) adjusting the pH value of the hydrochloric acid eluent to 6.5-7 by using liquid alkali, passing through a resin column filled with 100-120 kg of acid type resin (Purolite C100E) and 250-300 kg of alkali type resin (Purolite A600), and removing inorganic salts and impurities to obtain a pure product water solution;
6) reduced pressure distillation is carried out to obtain 85 percent choline alfoscerate.
Further, the chlorinated choline phosphate salt is calcium choline phosphate, sodium choline phosphate, potassium choline phosphate, and the (R) - (-) -3-halo-1, 2-propanediol is (R) - (-) -3-chloro-1, 2-propanediol, (R) - (-) -3-bromo-1, 2-propanediol, or (R) - (-) -3-iodo-1, 2-propanediol.
Further, the mole ratio of the chlorinated choline phosphate salt to the (R) - (-) -3-halo-1, 2-propanediol is 1: 1.4 to 1.6, preferably 1: 1.5.
further, the lower aliphatic alcohol is methanol, ethanol or isopropanol.
Further, the reaction temperature is the reflux temperature of the lower aliphatic alcohol, and the reaction time is 24-48 hours.
Further, the modified resin column is prepared by mixing halogenated metal salt and resin in a mass ratio of 1: 3-7, preferably 1: 5.
further, the halogenated metal salt modified resin column resin is AB-8, NKA, DM130, and the halogenated metal salt is calcium chloride, magnesium chloride, zinc chloride, cadmium chloride, magnesium bromide, zinc bromide and the like.
Further, the ion exchange resin is 001 × 7 in acid form, 100E in PuroliteC and 001 in D001 in alkali form, 201 × 7 in Purolite a600, D201 and D301 in mass ratio of 1: 2-1: 3, preferably 1: 2.5.
Compared with the prior art, the invention has the following beneficial effects: the method is based on the industrialization angle, takes low-grade fatty alcohol and water as solvents, is completely reused, extremely accords with the concept of modern green chemical industry, reduces the production cost, performs primary purification through a modified resin column, performs final purification through an anion-cation resin column, takes chlorinated phosphorylcholine salt and (R) - (-) -3-halogenated-1, 2-propylene glycol as substrates, performs reaction in low-grade fatty alcohol, and performs purification through a halogenated metal salt modified resin column and the anion-cation resin respectively, so as to obtain the glycerophosphorylcholine with higher purity.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the principles of the invention and not to limit the invention. In the drawings:
FIG. 1 is the principal chemical reaction scheme of the present invention.
In the figure: x is chlorine, bromine or iodine; y is sodium, potassium or calcium.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Referring to fig. 1, the present invention provides a technical solution: a method for industrially producing choline alfoscerate comprises the following steps:
example 1:
an industrial production method of choline alfoscerate, a method for industrial production of choline alfoscerate, which takes choline alfoscerate and (R) - (-) -3-halo-1, 2-propanediol as substrates, reacts in lower aliphatic alcohol, and is purified by halogenating metal salt modified resin column and anion and cation resin, respectively, thus obtaining high-purity choline alfoscerate.
The method mainly comprises the following steps:
1) 160 kg of choline chloride sodium salt and 90 kg of (R) - (-) -3-chloro-1, 2-propanediol are reacted in 1200 kg of absolute methanol solution, and after the reaction is finished for 30 hours, the filtrate is obtained by centrifugation.
2) Distilling off low-grade fatty alcohol in the filtrate, and recovering the low-grade fatty alcohol to obtain a viscous material.
3) And (3) adding 800kg of deionized water to dissolve the viscous material, adding 10-30 kg of activated carbon to decolor, and filtering to obtain an aqueous solution.
4) Passing through a modified resin column filled with 400kg of mixed magnesium chloride resin, eluting impurities by 1000 kg of deionized water, eluting a product by 1000 kg of 5% hydrochloric acid, and collecting hydrochloric acid eluent.
5) Adjusting the pH value of the hydrochloric acid eluent to 6.5-7 by using liquid alkali, passing through a resin column filled with 100-120 kg of acid type resin (Purolite C100E) and 150-300 kg of alkali type resin (Purolite A600), and removing inorganic salts and impurities to obtain a pure product water solution.
6) Reduced pressure distillation gave 85% (yield 86%, purity 99.5%, beta-2.7, pH 6.0) of glycerophosphorylcholine.
Further, the choline chloride phosphate salt is calcium choline phosphate, sodium choline phosphate, potassium choline phosphate, and the (R) - (-) -3-halo-1, 2-propanediol is (R) - (-) -3-chloro-1, 2-propanediol, (R) - (-) -3-bromo-1, 2-propanediol, or (R) - (-) -3-iodo-1, 2-propanediol.
Further, the mole ratio of the chlorinated choline phosphate salt and the (R) - (-) -3-halogen-1, 2-propanediol is 1: 1.4 to 1.6, preferably 1: 1.5.
further, the lower aliphatic alcohol is methanol, ethanol, isopropanol.
Further, the reaction temperature is the reflux temperature of the lower aliphatic alcohol, and the reaction time is 24-48 hours.
Further, the modified resin column is prepared by mixing the halogenated metal salt and the resin in a mass ratio of 1: 3-7, preferably 1: 5.
further, the resin column modified by halogenated metal salt is AB-8, NKA, DM130, and the halogenated metal salt is calcium chloride, magnesium chloride, zinc chloride, cadmium chloride, magnesium bromide, zinc bromide, etc.
Further, the ion exchange resin is 001 × 7 in acid form, PuroliteC100E, D001 in alkali form, 201 × 7 in Purolite a600, D201, D301 in mass ratio of 1: 2-1: 3, preferably 1: 2.5.
Example 2:
an industrial production method of choline alfoscerate, a method for industrial production of choline alfoscerate, which takes choline alfoscerate and (R) - (-) -3-halo-1, 2-propanediol as substrates, reacts in lower aliphatic alcohol, and is purified by halogenating metal salt modified resin column and anion and cation resin, respectively, thus obtaining high-purity choline alfoscerate.
The method mainly comprises the following steps:
1) 80 kg of choline chloride sodium phosphate and 45 kg of (R) - (-) -3-chloro-1, 2-propanediol are reacted in 600 kg of anhydrous methanol solution, and after the reaction is finished for 30 hours, the filtrate is obtained by centrifugation.
2) Distilling off low-grade fatty alcohol in the filtrate, and recovering the low-grade fatty alcohol to obtain a viscous material.
3) And adding 400kg of deionized water to dissolve the viscous material, adding 10-30 kg of activated carbon to decolor, and filtering to obtain an aqueous solution.
4) Passing through a modified resin column filled with 200 kg of mixed magnesium chloride resin, eluting impurities with 500 kg of deionized water, eluting the product with 500 kg of 5% hydrochloric acid, and collecting the hydrochloric acid eluate.
5) Adjusting the pH value of the hydrochloric acid eluent to 6.5-7 by using liquid alkali, passing through a resin column filled with 100-120 kg of acid type resin (Purolite C100E) and 150-300 kg of alkali type resin (Purolite A600), and removing inorganic salts and impurities to obtain a pure product water solution.
6) Reduced pressure distillation gave 85% (yield 86%, purity 99.5%, beta-2.7, pH 6.0) of glycerophosphorylcholine.
Further, the choline chloride phosphate salt is calcium choline phosphate, sodium choline phosphate, potassium choline phosphate, and the (R) - (-) -3-halo-1, 2-propanediol is (R) - (-) -3-chloro-1, 2-propanediol, (R) - (-) -3-bromo-1, 2-propanediol, or (R) - (-) -3-iodo-1, 2-propanediol.
Further, the mole ratio of the chlorinated choline phosphate salt and the (R) - (-) -3-halogen-1, 2-propanediol is 1: 1.4 to 1.6, preferably 1: 1.5.
further, the lower aliphatic alcohol is methanol, ethanol, isopropanol.
Further, the reaction temperature is the reflux temperature of the lower aliphatic alcohol, and the reaction time is 24-48 hours.
Further, the modified resin column is prepared by mixing the halogenated metal salt and the resin in a mass ratio of 1: 3-7, preferably 1: 5.
further, the resin column modified by halogenated metal salt is AB-8, NKA, DM130, and the halogenated metal salt is calcium chloride, magnesium chloride, zinc chloride, cadmium chloride, magnesium bromide, zinc bromide, etc.
Further, the ion exchange resin is 001 × 7 in acid form, PuroliteC100E, D001 in alkali form, 201 × 7 in Purolite a600, D201, D301 in mass ratio of 1: 2-1: 3, preferably 1: 2.5.
Based on the above, the present invention has the advantages that, from the industrial point of view, the present invention uses lower aliphatic alcohol and water as solvents, and the whole process is reused, which extremely accords with the idea of modern green chemical industry, reduces the production cost, primarily purifying by a modified resin column, finally purifying by an anion-cation resin column, taking chlorinated choline phosphate and (R) - (-) -3-halogenated-1, 2-propylene glycol as substrates, reacting in lower aliphatic alcohol, purifying by halogenated metal salt modified resin column and anion-cation resin respectively, compared with the existing industrialized technology, the technology provided by the invention is environment-friendly, simple to operate and low in cost, the yield reaches more than 85%, the purity is more than 99%, the optical rotation is-2.4 to-2.9, and the PH is 5.0-7.0.
It is noted that, herein, relational terms such as first and second, and the like may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Also, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (8)
1. A method for industrially producing choline alfoscerate is characterized in that: choline chlorophosphate and (R) - (-) -3-halogeno-1, 2-propanediol are used as substrates, and the products are reacted in lower aliphatic alcohol and purified by a halogenated metal salt modified resin column and anion-cation resin respectively, so that the high-purity glycerophosphorylcholine is obtained.
The method mainly comprises the following steps:
1) choline chloride potassium phosphate and (R) - (-) -3-chloro-1, 2-propanediol in a molar ratio of 1: 1.5, mixing, reacting in a low-grade fatty alcohol solution, performing reflux reaction for 24-48 hours, and centrifuging to obtain a filtrate;
2) distilling off low-grade fatty alcohol in the filtrate, and recovering the low-grade fatty alcohol to obtain a viscous material;
3) adding deionized water to dissolve the viscous material, adding activated carbon to decolorize, and filtering to obtain water solution;
4) passing through a halogenated metal salt modified resin column, eluting impurities by deionized water, eluting a 5% hydrochloric acid eluate to obtain a product, and collecting the hydrochloric acid eluate;
5) adjusting the pH value of the hydrochloric acid eluent to 6.5-7 by using liquid alkali, passing through a resin column filled with 100-120 kg of acid type resin (Purolite 100E) and 250-300 kg of alkali type resin (Purolite A600), and removing inorganic salts and impurities to obtain a pure product water solution;
6) reduced pressure distillation is carried out to obtain 85 percent choline alfoscerate.
2. The method for industrially producing choline alfoscerate according to claim 1, wherein: the chlorinated choline phosphate salt is calcium choline phosphate, sodium choline phosphate and potassium choline phosphate, and the (R) - (-) -3-halogen-1, 2-propanediol is (R) - (-) -3-chlorine-1, 2-propanediol, (R) - (-) -3-bromine-1, 2-propanediol and (R) - (-) -3-iodine-1, 2-propanediol.
3. The method for industrially producing choline alfoscerate according to claim 1, wherein: the mole ratio of the chlorinated choline phosphate salt to the (R) - (-) -3-halogen-1, 2-propylene glycol is 1: 1.4 to 1.6, preferably 1: 1.5.
4. the method for industrially producing choline alfoscerate according to claim 1, wherein: the lower aliphatic alcohol is methanol, ethanol, isopropanol.
5. The method for industrially producing choline alfoscerate according to claim 1, wherein: the reaction temperature is the reflux temperature of the lower aliphatic alcohol, and the reaction time is 24-48 hours.
6. The method for industrially producing choline alfoscerate according to claim 1, wherein: the modified resin column is prepared by mixing halogenated metal salt and resin in a mass ratio of 1: 3-7, preferably 1: 5.
7. the method for industrially producing choline alfoscerate according to claim 1, wherein: the halogenated metal salt modified resin column resin is AB-8, NKA and DM130, and the halogenated metal salt is calcium chloride, magnesium chloride, zinc chloride, cadmium chloride, magnesium bromide, zinc bromide and the like.
8. The method for industrially producing choline alfoscerate according to claim 1, wherein: the ion exchange resin is 001 multiplied by 7 in acid form, Purolite C100E and D001 in alkali form, 201 multiplied by 7 in alkali form, Purolite A600, D201 and D301 in mass ratio of 1: 2-1: 3, preferably 1: 2.5.
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